Impact of ocular microbiome, immune response and Chlamydiae on trachoma following MDA

MDA 后眼部微生物组、免疫反应和衣原体对沙眼的影响

• 批准号: 10519058
• 负责人: DEBORAH Anne DEAN
• 金额: $ 79.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10519058
• 关键词: 10 year old; Adoption; Affect; Africa; Age; Algorithms; Anti-Inflammatory Agents; Antibiotics; Australia; Azithromycin; Biological Response Modifiers; Blindness; Central America; Characteristics; Child; Chlamydia; Chlamydia trachomatis; Communicable Diseases; Communities; Country; Data; Development; Diagnostic; Disease; Epidemiologist; Ethiopia; Ethiopian; Eye; Eyelash; Face; Far East; Genetic; Genitourinary system; Genomics; Geography; Hygiene; Immune; Immune response; Infection; Inflammation; Inflammation Mediators; Inflammatory Response; Intervention; Knowledge; Metagenomics; Methods; Middle East; Minority; Modeling; Mutation; Natural History; Operative Surgical Procedures; Organism; Pathogenesis; Pathogenicity; Persons; Pharmaceutical Preparations; Phylogeny; Population; Populations at Risk; Price; Productivity; Public Health; Regimen; Research; Resolution; Risk; Role; Sampling; Sanitation; Severity of illness; Shotgun Sequencing; South America; South Sudan; Structure; Study Subject; Taxonomy; Therapeutic; Time; Trachoma; Vision; Water; Work; World Health Organization; Zoonoses; azithromycin resistance; base; burden of illness; cohort; design; disorder control; dysbiosis; genetic resistance; genome sequencing; health disparity; host microbiota; improved; innovation; member; metagenome; microbial composition; microbial host; microbiome; microbiota; neglect; novel therapeutic intervention; ocular microbiome; pathogen; pathogen genomics; prevent; programs; resistance gene; sex; therapy duration; transmission process; treatment duration; whole genome

PROJECT SUMMARY Chlamydia trachomatis (Ct) is the leading cause of infectious blindness in the world today. The World Health Organization (WHO) estimates that there are over 142 million people at risk of irreversible loss of sight. This figure likely underestimates the true numbers as it is difficult to account for all communities that are affected globally. The ocular disease caused by Ct is called trachoma and carries an annual price tag of approximately $8 billion from lost productivity. The highest concentrations of this neglected disease include 37 countries in Africa, the Middle East, Asia, and Central and South America along with Australia. Africa has over 89% of the world’s known trachoma cases, reflecting a major region of health disparity. The WHO developed the SAFE strategy to eliminate trachoma as a public health problem by the year 2020. SAFE stands for: Surgery to correct in-turned eyelashes (known as Trachomatous Trichiasis or TT); Antibiotics to treat Ct; Facial cleanliness to improve hygiene, and Environmental improvements to reduce transmission. The A part of SAFE includes Mass Drug Administration (MDA) with azithromycin and has been used in many countries. Ten endemic or hypoendemic countries have been validated by WHO as being trachoma free. However, 6 endemic and 38 hyperendemic countries have not, although they have received 5 to over 10 rounds of MDA. The highest burden of disease is in Ethiopia and South Sudan where ~30-50% of children under 10 years of age have active trachoma, and the reasons for this remain unclear. Trachoma as a public health concern will not be eliminated until we understand why there is ongoing active trachoma following multiple rounds of MDA in hyperendemic countries. Our unifying hypothesis, therefore, is that the natural history of trachoma is defined by the interaction of the ocular microbiome, immune responses and pathogen populations (both Ct and non-Ct) that are influenced by MDA. While there is a growing body of research on the ocular microbiome, few studies have evaluated differences in microbiota composition between healthy and trachomatous eyes and none have looked at the influence of Ct infection. We will employ metagenome shotgun sequencing (MSS) to understand healthy, dysbiotic and chlamydial-associated microbiota in addition to immune responses and pathogen genomic characteristics for a cohort residing in the trachoma hyperendemic Amhara Region of Ethiopia. We aim to: 1) Examine Ct infections based on whole genome sequencing; 2) Identify taxonomic diversity and abundance of ocular microbiota among subjects with and without Chlamydia and their association with trachomatous disease; and 3) Determine host microbiota/immune response profiles associated with and without Chlamydia, and develop models to predict trachoma post MDA. This work will naturally transition to improving chlamydial diagnostics that utilize MSS methods, and developing interventions that, given the ineffective antibiotic regimens to date, may include novel therapeutic strategies and/or revised treatment duration to decrease and eliminate hyperendemic trachoma among at risk populations in Africa that have the greatest need for intervention.

项目总结 沙眼衣原体(Ct)是当今世界导致传染性失明的主要原因。《世界卫生》 世界卫生组织(WHO)估计，有超过1.42亿人面临不可逆转的失明风险。这 数字可能低估了真实数字，因为很难计算所有受影响的社区 全球范围内。由CT引起的眼部疾病被称为沙眼，每年的费用约为 80亿美元的生产力损失。这种被忽视的疾病最集中的国家包括37个国家 非洲、中东、亚洲、中南美洲和澳大利亚。非洲有超过%的 世界上已知的沙眼病例，反映了一个主要地区的健康差距。世界卫生组织开发了安全 到2020年消除沙眼这一公共卫生问题的战略。SAFE代表：手术矫正 内翻睫毛(称为沙眼倒睫病或TT)；治疗CT的抗生素；面部清洁 改善卫生，改善环境，减少传播。外管局的A部分包括群众 药品监督管理局(MDA)与阿奇霉素一起使用，已在许多国家使用。十种地方病或 低流行国家已被世卫组织确认为无沙眼。然而，6例地方性和38例地方性 高流行国家没有，尽管它们已经接受了5至10轮以上的丙二醛。最高的负担 在埃塞俄比亚和南苏丹，约30%-50%的10岁以下儿童患有 沙眼，其原因尚不清楚。沙眼作为一个公共卫生问题不会被根除 直到我们了解为什么在高地方性疾病的多轮丙二醛治疗后仍会出现活动性沙眼 国家。因此，我们的统一假设是，沙眼的自然病史是由相互作用定义的。 眼部微生物群、免疫反应和病原体种群(Ct和非Ct)受到影响 由丙二醛。虽然对眼部微生物群的研究越来越多，但很少有研究评估 健康和沙眼之间微生物区系组成的差异以及没有人观察过 CT感染的影响。我们将使用超基因组鸟枪测序(MSS)来理解健康、 除免疫反应和病原体基因组外的非生物和衣原体相关微生物区系 居住在埃塞俄比亚流行沙眼的阿姆哈拉地区的一个队列的特征。我们的目标是：1) 基于全基因组测序检查CT感染；2)确定分类多样性和丰度 衣原体感染者和非衣原体感染者的眼部微生物区系及其与沙眼疾病的关系； 以及3)确定与衣原体相关和不与衣原体相关的宿主微生物区系/免疫反应概况，以及 开发预测丙二醛后沙眼的模型。这项工作自然会过渡到改善衣原体 利用MSS方法的诊断，以及开发干预措施，在给定无效的抗生素方案的情况下 到目前为止，可能包括新的治疗策略和/或修订的治疗持续时间，以减少和消除 高度地方性沙眼在非洲最需要干预的高危人群中流行。